The long-term objective is to determine the immunologic and inflammatory responses that have an impact on the progression and resistance to mycoplasma respiratory disease, and apply this information to development of effective immunotherapies against mycoplasma diseases. Mycoplasmas are a major cause of lung disease in humans. Immune responses against mycoplasma can either be protective or promote inflammatory disease. These studies take advantage, of a murine model of mycoplasma respiratory disease due to M. pulmonis. This is a pathogen in its natural host and causes disease similar to human mycoplasma pneumonia. In the past award period, T cell responses were shown to be critical determinants in mycoplasma respiratory disease pathogenesis. This proposal addresses the following: 1) How does generation of Th cell responses during mycoplasma disease pathogenesis or after immunization influence disease progression? Th2 responses are hypothesized to be immunopathologic in mycoplasma lung disease while Thl responses contribute to resistance. 2) What is the role of anti-mycoplasma CD8+ T cells in dampening disease? CD8+ T cell responses against mycoplasma are hypothesized to regulate Th cell responses involved in the pathogenesis of inflammatory lesions; 3) Do CD4+CD25+ Treg cells have an effect on T cell responses that influence progression of mycoplasma disease? It is hypothesize that CD4+CD25+ Treg cells modulates adaptive T cell responses against mycoplasma infection, which may contribute to persistence of infection while dampening immune-mediated inflammation. 4) What is the influence of T cell populations on murine Mycoplasma pneumoniae disease? To begin to examine the role of T cells in disease due to the human pathogen, M. pneumoniae, we will take advantage of a murine model of this infection. We hypothesize that the immune mechanisms found in disease due to the natural pathogen, M. pulmonis, will be similarly activated and play similar roles in M. pneumoniae disease in mice. The experimental designs are: 1) Th cells from normal and cytokine knockout mice will be adoptively transferred and their impact on mycoplasma disease examined. Mycoplasma-specific Th subset cell lines will similarly be used; 2) In vitro culture with Th cells and adoptive transfer of will be used examine the impact of CD8+ T cells on mycoplasma-specific Th cell activation; 3) CD25+ cells will be depleted in mice using specific antibody, and the persistence of infection and pathogenesis of disease will be examined in IL-10 knockout mice, and in vivo treatment with antibodies will examined. In addition, reconstituion of nude mice with CD4+CD25+ T cells and Th cells will be used to examine the effect on mycoplasma disease; and 4) Studies will be done in parallel to determine the role of T cells in a murine model of M. pneumoniae disease.